Chemical agents

ABSTRACT

New chemical compounds, bis quaternary carbamates, having the generic  fora: ##STR1## wherein X is one equivalent of an anion selected from monovalent or polyvalent anions, wherein n is 1 to 8, and wherein R, R&#39; are aliphatic radicals selected from the group consisting of methyl, ethyl, propyl, and butyl, and having utility as toxic agents.

This invention relates to the synthesis of new toxic chemical compoundswhich are useful as chemical warfare agents. More particularly, ourinvention is concerned with novel compounds produced by means of aquaternizing reaction.

The chemical agents act mostly on the peripheral cholinergic nervoussystem which includes the motor nerves, the preganglionic fibers, theganglia, the postganglionic parasympathetic fibers, and neuromuscularfunctions. The transmission of impulses along a nerve or from nervefibers to muscle fibers or secretory cells or from one nerve fiber toanother across synapses in ganglia is thought to involve chemicalchanges either directly or as the source of potential differences.

Quaternary ammonium compounds in general are known to be physiologicallyactive materials. Mainly because of their positively charged "onium"centers, they are attracted by anionic sites in animal tissues,particularly those situated at cell surfaces and interfaces. They caninduce physiological responses that mimic or antagonize the action ofacetylchlorine as a result of their interaction with the variousphysiological receptor sites of acetylcholine, especially those atmembranes of muscle cells. They also combine with enzymes such asacetylcholinesterase, other esterases, acetylcholineacetylase, etc.,thus inhibiting their participation in the biological processes.

One of the significant anatomical differences between the neuromuscularjunctions and other acetylchlorine receptive sites is the absence of amembrane barrier or a sheath such as envelops the ganglia. Thecompartive ease of accessibility of the neuromuscular junctions to"onium" compounds contributes to their relatively fast onset of actionand partly explains why in many instances relatively small doses sufficeto evoke physiological actions that modify or interrupt normalneuromuscular impulse transmission.

Depending on their chemical structures, different quaternary compoundsinterfere with the mechanism of impulse transmission in differentmanners and the final physiological effects can vary considerably. Somequaternary ammonium compounds are used as therapeutic agents, others areknown to be lethal. The magnitude, accessibility, and distribution ofthe positive charges in quaternary compounds are believed to be the keyfactors in the determination of specificity of action. Recognition ofthese facts explains the strikingly different physiological behavior sooften observed when structurally very closely related compounds arecompared. The nature of the groups attached to the quaternary nitrogensinfluences the distribution of the cationic charges. The length andbranching of aliphatic chains and the volume and configuration ofaromatic and alicyclic rings have a bearing on the ease or difficulty ofapproach to the specific receptor sites. Electrophilic and nucleophiliccenters in the molecule will insert their inductive effects on thepositive charges and can also aid in the interaction with the "esteraticsites" of various enzymes. These sites are believed to be located inclose vicinity to the anionic sites of the active centers. Substitutionof different functional groups influence association and hydration andmay considerably change the solubilities in physiological media. Inbis-quaternary and poly-quaternary compounds, the distance between theelectric charges must be considered. These factors contribute to governthe rate and reversibility of the chemical reactions involved, andcontribute to determine the final physiological responses.

Our chemical agents interfere with the normal process of neuromuscularimpulse transmission and thus disrupt the propagation of impulses fromnerves to muscles. We have also found these compounds to be extremelytoxic at relatively low dose levels in various animals.

The object of this invention is to synthesize new lethal agents usefulin chemical warfare in high yields wherein said products are well suitedfor industrial scale manufacture.

Other objects of and uses for the invention will in part be obvious andwill in part appear hereinafter in the following detailed descriptionthereof.

Our compounds may be employed in any munition suitable for handling arelatively non-volatile toxic agent such as bombs, shells, spray tanks,rockets, missiles, aerosol generators, and others.

In accordance with our invention, the tertiary aminofunction of analiphatic aminonitrile, such as cyanomethyldimethylamine, wasquaternized withN-(10-bromodecyl)-N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammoniumbromide in a solvent, such as acetonitrile, under reflux conditions.Reflux was maintained for approximately 24 hours. After the reactionmixture was allowed to cool to room temperature, a solvent, such asacetone, was added. An oily material separated. The supernatant solventmixture was decanted and the remaining oil stirred in a boiling solventsuch as acetone for 15 minutes. The mixture was allowed to cool to roomtemperature, the acetone decanted and the gummy residue dissolved in asolvent such as methanol. This solution was treated with decolorizingcarbon and then concentrated to a few milliliters. The concentrate wasplaced in an apparatus that was kept under reduced pressure. Theresultant white crystalline material constitutes the new compounds ofthe present invention which may be represented by the following genericformula: ##STR2## wherein X is an equivalent of an anion selected frommonovalent and polyvalent anions, wherein n is 1-8, and wherein R, R'are aliphatic radicals selected from the group consisting of methyl,ethyl, propyl, and butyl.

The procedure used for the preparation of the new toxic materials isschematically shown below: ##STR3## wherein X is a halide ion,preferably bromide, and wherein n and R, R' are as defined above.

If compounds are desired in which X is other than a halide ion, theabove quaternary compounds are treated with the desired acid by simpleexchange reactions as set forth below.

EXAMPLE 1

N-(10-bromodecyl)-N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammoniumbromide (1.05 g) and cyanomethyldimethylamine (0.34 g) were dissolved in5 ml of acetonitrile and refluxed for 24 hours. The reaction mixture wasthen allowed to cool to room temperature and 50 ml of acetone was added.The supernatant solvent mixture was decanted and the remaining oil wasstirred in 50 ml of boiling acetone for 15 minutes. The mixture wasallowed to cool to room temperature, the acetone decanted, and the gummyresidue dissolved in 15 ml of methanol. The solution was treated withdecolorizing charcoal and then concentrated to a few milliliters. Theconcentrate was placed for 4 hours in an apparatus that was kept underreduced pressure (1 mm) at 80° C. The product,1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanedibromide, (0.6 g) was obtained as a white crystalline material.

Analysis for C₂₅ H₄₅ Br₂ N₅ O₂ : Calcd: C, 49.4; H, 7.5; Br, 26.3.Found: C, 49.3; H, 7.5; Br, 26.1.

    ______________________________________    TOXICITY    IV LD.sub.50    Rabbits        Mice    ______________________________________    0.0056 mg/kg   0.010 mg/kg    ______________________________________

EXAMPLE 2

N-(10-bromodecyl)-N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammoniumbromide (1.05 g) and (3-cyanopropyl)dimethylamine (0.56 g) weredissolved in 10 ml of acetonitrile and refluxed for 24 hours. After thereaction mixture was allowed to cool to room temperature, 50 ml ofacetone was added. The supernatant solvent mixture was decanted and theremaining oil stirred in 50 ml of boiling acetone. The mixture wasallowed to cool to room temperature, the acetone decanted, and the gummyresidue dissolved in 15 ml of methanol. The solution was treated withdecolorizing carbon and then concentrated to a few milliliters. Theconcentrate was placed for 4 hours in an apparatus that was kept underreduced pressure (1 mm) at 80° C. The product,1-[N,N-dimethyl-N-(3-cyanopropyl)ammonio]-10-[N-(3-dimethylcarbamoxy-.alpha.-picolinyl)-N,N-dimethylammonio]decanedibromide (1 g), was obtained as a deliquescent white crystallinematerial. Because of its deliquescency a sample of the compound wasconverted to and analyzed as the tetraphenylboronate salt. The abovedibromide salt was dissolved in water and to this solution an aqueoussolution of sodium tetraphenylboron (in molar excess) was added. Thesolid that formed was collected on a filter, washed a few times withwater, and then dried. The tetraphenylboronate salt melted between 67°and 69° C.

Analysis for C₇₅ H₈₉ B₂ N₅ O₂ : Calcd: C, 80.8; H, 8.1; N, 6.3. Found:C, 80.8; H, 8.4; N, 6.4.

    ______________________________________    TOXICITY    IV LD.sub.50    Rabbits        Mice    ______________________________________    0.0056 mg/kg   0.011 mg/kg    ______________________________________

Method of Preparation ofN-(10-bromodecyl)-N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammoniumbromide

A solution of 62.3 g of2-dimethylaminomethyl-3-dimethylcarbamoxypyridine and 251 g of 1,10dibromodecane was refluxed for 7 days in 1 liter of anhydrous ether. Theproduct that formed was collected on a filter, washed with two 100 mlportions of anhydrous ether, and dissolved in 1 liter of acetone. Theacetone solution was treated with decolorizing carbon and filtered. Thefiltrate was concentrated under reduced pressure to approximately 200ml. Ether was added until the solution became turbid. The mixture wasthen seeded and chilled overnight. The resultant crystalline product wascollected and further purified by recrystallization from ethyl acetate.The pure product was dried in vacuo for 2 hours, yielding 76 g ofmaterial, m.p. 90° to 92° C.

Analysis for C₂₁ H₃₇ Br₂ N₃ O₂ : Calcd: C, 48.2; H, 7.1; Br⁻ (ionic),15.3; O, 6.1. Found: C, 48.2; H, 7.0; Br⁻ (ionic), 15.2; O, 6.2.

The compounds that are representative of our invention are listed belowby name and chemical structure. ##STR4##

We have shown preferred compounds in which the anion is limited to thehalogen moiety, in particular the bromide, since the bromoalkanes aregood quaternizing agents. In general, however, it is only necessary thatthe anions merely have to meet the requirement of being capable offorming a stable salt with the quaternary nitrogen. Thus the halogenions can be exchanged with other anions of relatively strong monovalentor polyvalent acid by conventional methods. For example, if X⁻ is abromide in the final product, a solution of the compound can be treatedwith a basic ion exchange resin or mixed with silver oxide andsubsequently the desired acid is added to the quaternary hydroxidesolution. Anions other than the halogens may also be obtained bymetathesis with the halide form of the quaternary ammonium compound.Suitable as representations of X⁻ are the anions hydrogen oxalate,perchlorate, nitrate, tetraphenylboronate, hydrogen sulfate.Representative examples of these additional endproducts are:

1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanedi(hydrogen oxalate).

1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanediperchlorate.

1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanedinitrate.

1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanedi(tetraphenylboronate).

1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanedi(hydrogen sulfate).

We claim:
 1. New chemical compounds having the generic formula: ##STR5##wherein n is 1-8, wherein R, R' are aliphatic radicals selected rom thegroup consisting of methyl, ethyl, propyl, and butyl, and wherein X isone equivalent of an anion selected from monovalent and polyvalentanions; said anions being selected from the group consisting of halide,hydrogen oxalate, perchlorate, hydrogen sulfate, nitrate, andtetraphenylboronate.
 2. New chemical compounds selected from the groupof compounds having the names1-(N,N-dimethyl-N-cyanomethylammonio)-10-[N-(3-dimethylcarbamoxy-α-picolinyl)-N,N-dimethylammonio]decanedibromide and1-[N,N-dimethyl-N-(3-cyanopropyl)ammonio]-10-[N-(3-dimethylcarbamoxy-.alpha.-picolinyl)-N,N-dimethylammonio]decanedibromide.